Many diseases that are mostly localized in a certain tissue are treated with systemically administered drugs. A well-known example of standard cancer therapy is a systemic chemotherapy coming along with significant side effects for the patient due to undesired biodistribution and toxicity. The therapeutic window of these drugs is usually defined by the minimal required therapeutic concentration in the diseased tissue on the one hand, and the toxic effects in non-targeted organs, e.g. liver, spleen, on the other.
Localized treatment by, for example, local release of cytostatics from nanocarriers promises a more efficient treatment and a larger therapeutic window compared to standard therapeutics. Localized drug delivery is also important if other therapeutic options such as surgery are too risky as is often the case for liver cancers. Localized drug delivery can also become the preferred treatment option for many indications in cardiovascular disease (CVD), such as atherosclerosis in the coronary arteries.
Medical imaging technology, such as magnetic resonance imaging (MRI) or ultrasound imaging, can not only be used for treatment planning, but also to control local drug delivery under image guidance. Focused ultrasound is the method of choice to induce local drug delivery, since it offers several advantages. This technique is non-invasive, can be focused on the diseased tissue and shows only very limited adverse effects on the surrounding tissue. Ultrasound can provide two kinds of trigger for drug delivery. First, the target tissue can be heated in a controlled way with a precision of about half a degree centigrade in a temperature range from body temperature up to 100° C. Second, the ultrasound waves are strong pressure oscillations that provide a stimulus for drug delivery based on mechanical forces.
The skilled person faces several challenges in providing carrier systems for the release of materials such as drugs or imaging compounds. Thus, e.g., the carrier system needs to be designed such that it can be loaded with a sufficient amount of said materials. Particularly if the material to be released comprises drugs, the carrier system should be sensitive to an external stimulus, such as (local) changes in temperature or pressure which allow for quick and localized release of a drug. Moreover, the drug delivery process needs to be under full control, i.e. the drug release at the site of treatment must be measurable in vivo, the amount and rate of drug release should serve as an input parameter for the determination of the subsequent stimulus application, hence drug delivery could be controlled in an image-guided feedback loop.
A significant improvement in the efficacy of liposomal drug therapies can be obtained by triggering the release of drugs by means of an external stimulus. One approach to trigger the release of encapsulated molecules is the use of temperature-sensitive liposomes. 1 In this case, the release of the drug occurs above the melting phase transition temperature (Tm) of the liposome membrane. At Tm, structural changes in the lipid membrane occur as it transfers from a gel-like to the liquid state phase. This transition leads to a distinct increase in the permeability of the membrane for solutes and water. The incorporation of phosphatidylcholines, such as lyso-PC, acetylated MPPC, and platelet activation factor (PAF), in the bilayer of liposomes has a pronounced effect on the properties of the liposomes. In 1988, Bratton et al. demonstrated that these lipids can be utilized to decrease the Tm of dipalmitoylphosphatidylcholine (DPPC)-based liposomes.2 Needham et al. have designed low temperature-sensitive liposomes (LTSLs) composed of lyso-PC/DPPC/DPPE-PEG2000 that release encapsulated doxorubicin (ThermoDox®) in a matter of seconds in response to mild hyperthermic conditions (39-42° C.).3 The quick release of aqueous solutes from the interior of these temperature-sensitive systems at temperatures close to the Tm was ascribed to the formation of transient pores. These pores are thermodynamically stable in the presence of micelle-forming phospholipids, such as lyso-PC and PEGylated phospholipids. Moreover, the transient pore formation has been ascribed to the accumulation of lysolipids by lateral diffusion within the lipid bilayer. Preclinical experiments with lyso-PC (R═C15H31, FIG. 1) based LTSLs loaded with doxorubicin in combination with an externally applied regional temperature increase clearly showed an improved efficacy of temperature-induced drug delivery.3,4 Instead of relying on liposomal accumulation in the tumor, hyperthermia was applied during the first hour after injection of the temperature-sensitive liposomal formulation of doxorubicin. This cytostatic drug was rapidly released in the microvasculature of the tumor and subsequently taken up by the tumor cells. Although lyso-PC based LTSLs loaded with doxorubicin have been successfully applied for drug delivery in combination with needle-based RF ablation, the stability of the liposomal formulation in plasma at 37° C. is suboptimal, showing up to 40% release of doxorubicin in 1 hour.
In the field of thermosensitive carriers for the local delivery, in a subject, of therapeutic and/or diagnostic agents, a need exists for providing carriers that are capable of longer circulation times, less leakage of their active contents at normal human body temperature (37° C.), and slower clearance from the system.
A reference addressing the foregoing desire is Lars H. Lindner et al., Clinical Cancer Research, 2004, Volume 10, Issue 6, pages 2168-2178. Herein liposomes are prepared on the basis of a third component, in addition to DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) and DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine). Said third component is DPPGOG (1,2-dipalmitoyl-sn-glycero-3-phospho ceroglycerol). The resulting three-component liposomes exhibit less leakage at 37° C. and a slower clearance from circulation.
The solution presented by Lindner et al. results in structurally more complex liposomes, and is limited to phospholipids. It would be desired to provide a synthetic tool to obtain thermosensitive liposomes that show an at least similar performance in avoiding leakage at 37° C., and an at least equally slow clearance, yet on the basis of a less complex liposome structure. Moreover, it would be desired to provide a synthetic tool to provide thermosensitive liposomes exhibiting a still slower clearance than the liposomes disclosed by Linder et al.